L-Arginine is a naturally occurring amino acid which plays many essential roles in the human body. One of these roles is as a substrate for nitric oxide synthase (NOS). Under normal conditions in the human body, nitric oxide (NO) has a half-life of only 3-5 seconds due to its swift inactivation by oxyhemoglobin when forming methemoglobin. Cyclic GMP is a downstream product of NO and controls most of the biological effects of NO, while the nitric oxide synthase (NOS) family of enzymes controls NO production. The three main types of NOS are: 1) inducible (iNOS); 2) neuronal (nNOS); and 3) endothelial (eNOS), all of which are found in the skin. All three of these isoforms require oxygen and nicotinamide adenine dinucleotide phosphate (NADPH) as substrates. Asymmetric dimethyl L-arginine (ADMA) is a basal inhibitor of the NOS family, and elevated levels of this substance have been found in cases of hypertension, hypercholesterolemia and other diseases associated with impaired vasodilatation. Elevating the concentration of L-arginine has been shown to overcome the inhibitory effect of ADMA without leading to increased NO production.
NO is known to play an important role in the physiology of the skin with effects on the microvasculature and blood flow, maintenance of barrier function, inflammatory skin conditions such as psoriasis, response to ultraviolet light and wound healing. Increased tissue NO concentration stimulates local vasodilatation and angiogenesis. However, NO diffuses freely so that it is difficult to maintain effective concentrations in the skin. An alternate strategy would be to elevate arginine concentration to increase the amount of substrate for NOS to use in the production of NO. However, arginine by itself has very poor skin penetration. One solution to this problem in other tissues has been to link L-arginine into oligomers from 7 to 15 units in length (oligoarginine). These compounds can effectively penetrate skin and increase concentrations of NO and have even been shown to transport covalently bound agents across cytoplasmic membranes (Cosmetic Formulations containing L-Arginine Oligomers, WO 03/072039 A2). However, it was not clear whether these benefits were due to the relatively unique transport properties of oligoarginine.
A specific example of the importance of angiogenesis in the skin is in the maintenance of healthy hair follicles. During the follicle life cycle, angiogenesis is largely controlled by a balance between pro- and anti-angiogenic factors. It has been shown that the anagen phase is especially dependent on pro-angiogenic factors to stimulate the increased blood flow necessary for the increased nutritional needs of the follicle (Cosmetic Formulations containing L-Arginine Oligomers, WO 03/072039 A2).
The invention described herein is directed to a strategy for providing therapeutic or cosmetic benefit to skin by topically applying arginine chemically bound to a second (non-oligoarginine) compound in order to increase transepithelial delivery of arginine through a combination of increased solubility and flux across the skin. The arginine heteromers of the invention can also provide other complementary or beneficial properties for the skin beyond those that are arginine-related.